1-alkyl-3-(hydroxyalkylamino) indole nu-oxides



United States Patent 1-ALKYL-3-(HYDROXYALKYLAMINO) INDOLE N-OIHDES William C. Anthony, Kalamazoo Township, Kalamazoo County, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Filed July 18, 1958, Ser. No. 749,334

9 Claims. (Cl. 260-2475) in (I) wherein R and R taken individually represent alkyl radicals containing from one to six carbon atoms, for example, methyl, ethyl, propyl, butyl, amyl, hexyl and isomeric forms thereof, and R and R taken together with N also represent a heterocyclic amino radical containing from five to seven atoms in the ring, not more than one of which, in addition to the amino nitrogen, is a hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen, the remaining atoms in the ring being carbon, such as pyrrolidino, Z-methylpyrrolidino, 2,2-dimethy1pyrrolidino, piperidino, methylpiperidino, ethylpipen'dino, morpholino, thiamorpholino, hexamethyleneimino, and the like, R is selected from the group consisting of hydrogen and an alkyl radical containing from one to six carbon atoms, for example, methyl, ethyl, propyl, butyl, amyl, hexyl and isomeric forms thereof, R represents an alkyl radical containing from one to six carbon atoms, for example, methyl, ethyl, propyl, butyl, amyl, hexyl and isomeric forms thereof and n is zero or one; and (2) acid addition salts thereof. The acid addition salts of the invention include the salts of compounds of the general Formula I with pharmacologically acceptable acids such as sulfuric, hydrochloric, hydrobromic, sulfamic, nitric, phosphoric, acetic, lactic, pyruvic, citric, tartaric, benzoic, p-toluenesulfonic acids, and the like.

It is an object of the invention to provide the novel compounds of the Formula I and their acid addition salts. Other objects of the invention will be apparent to those skilled in the art to which this invention pertains.

The compounds of the invention possess valuable pharmacodynamic properties, and in particular they possess diuretic activity, both orally and parenterally. The

diuretic activity of the compounds is significantly greater than that of the corresponding free amines from which they are derived by oxidation (as will be described hereafter). Further the compounds of the invention are markedly less toxic than the corresponding free amines. Hence the compounds of the invention exhibit a much higher therapeutic ratio than the corresponding amines from which they are derived. These differences in diuretic activity and toxicity are illustrated by the results quoted in the table below in which the toxicity as determined intraperitoneally in mice and the diuretic activity See determined orally in rats of two representative compounds of the invention and the corresponding amines from which they are derived are compared.

5 TABLE I Toxicity Diuretic Activity Percent Compound LD increase IP in Dose, in urine mifi, mgJkg. output mg. g. over controls 1-ethyl-3-(2-dlmethyl-amino-1 -hy- 5 42 droxyethyl) indole 133 10 60 32 1 -ethyl-3- (2-din1ethyl-amino -1 -hyg droxyethyl) indole N-oxide 650 m 121 20 130 1-methyl-3-(2-dimethyl-amino-1-hyg 20 droxyethyl) indole 744 20 108 40 1319 1-methyl-3-(2-dimethyl-amino-1-hy- 5 5 droxyethyl) indole N-oxlde 1,0oo $3 40 201 The compounds of the invention can be prepared by N ILA wherein R R R R and n have the significance hereinbefore defined, with hydrogen peroxide. The reaction is ordinarily conducted in the presence of a solvent such as methanol, ethanol, isopropanol, n-butanol, sec-butanol, benzene, chloroform and ethyl acetate, the preferred solvent being methanol. The hydrogen peroxide to be employed for reaction purposes can have a concentration varying from about five to about sixty percent, but it is preferable to employ hydrogen peroxide of a concentration of the order of thirty percent. It is desirable that an amount of hydrogen peroxide be employed in the reaction mixture which-is slightly in excess of the equimolecular amount required to react with the amine of Formula H. The amount of this excess advantageously should be not greater than about five percent. The reaction can be conducted over a range of temperatures from a lower limit of about zero degrees centigrade to an upper limit of about eighty degrees centigrade. The reaction is preferably conducted at a temperature of about twenty to thirty degrees centigrade.

When the reaction is conducted within the preferred temperature range and with the preferred amount of hydrogen peroxide, it is preferable to allow the reaction to proceed for an extended period of time, advantageously for at least one day or even several days, such as four or five days. After the reaction has been completed the excess hydrogen peroxide is removed by treating the reaction mixture With a reducing agent such as platinum oxide, palladium-on-charcoal, Raney nickel, inorganic hydrosulfites, for example, sodium hydrosulfite, and the like. The preferred reducing agent is platinum oxide. The reducing agent is separated from the reaction mixture, for

example, by filtration, and the desired reaction product, i.e., N-oxide of Formula I, is isolated by distillation of the solvent. The reaction product can be purified by conventional means, e.g., by recrystallization from a suitable solvent such as ethyl acetate.

The acid addition salts of the invention can beprepared by reacting a compound of Formula I with an R r 2,944,055 V ,7

equivalent of the appropriate acid. For example, a solution of the, desired acid addition salt can be prepared by mixing stoichiometric amounts of a compound of Formula I and the appropriate acid in the presence of water. Al-

ternatively, the compound of Formula I and the'apprd priateacid can be reacted in solution in a'suitahl'e or-. ganic solvent such as ether and a lower alkan'ohtor example, methanol, ethanol, isopropanol, and the like. However, when employing this method to form the salt of a compound of; Formula I with a strong mineral acid such as hydrochloric acid it'is essential to use not more than the stoichiometric quantity of acid; otherwise the exn has thevalue zero, and'R R and R have the sig- I ,nificance hereinbefore described, has been described indetailin US, 'Patent- 2,825,734; The' following 3-indole- 'alkanolamines are illustrative of those which can be used to prepare the compounds of the present invention: 1-methyl-3-(2-morpholino-1-hydroxyethyl)indole, l-ethyl-3e(2-dimethylamino-1 hydroxyethyl)indole, l=me hy -3-(l-d mct ylaminchydro yethy .)indcla.

1-buty1-3-(Z-dimethylaniino-l hydroiryethyl)indole and l-hei yl-3 (Z-dimethylamino-l-hydroxyet yl) indole.

vantageously carried out at temperatures between about 25 degrees and about 35 degress centigrade, although temperatures from about zero to about sixty degrees centigrade can also be employed. The reaction can be car- The compounds of Formula H in which n has the value it V (III) h rein R1, R2, R a R4 have. t s gnificance hereinbefore. de cribed. The ke on s of F m III an be prepared by reacting a 3-acylindole have the formula:

C-GHzR:

wherein R and R have-the significance hereinbefore defined,v form ldehyde and an amine /Ri HN' wherein R and R have the significance hereinbefore defined. Thereaction is generally carried out under acid conditions which conditions can be brought about by using the amine-in the form of'an acid'addition salt such the hydrochloride sulfate, and the like, or by the addition of an acid such as acetate, hydrochloric, phosphoric, sulfuric, hydrobromic, and the like, to the reaction mixture. 1 The acylindoles employed as starting materials 'can befprepared' .by processes outlined in Heterocyclic Compounds, EIderfield volume 3, page-44, 1952, John Wiley and: Sons, Inc. The reductionrofr the ketcnes of Formula III can be effected usingmethods well-knOWn in the art for the reduction of ketones to the corresponding secondary alcohols. The preferred, reducingagent is sofdiutn borohydiide. Using this agent the reduction is adried out in the presence of a solvent such as the lower alkanols, for example, methanol, ethanol, isopropanol, and the like, tetrahydrofuran, N-ethylmorpholine, dioxnd Water, the lower alkanols beingpreferred.

The S-indolealkanolamines of Formula II in which R represents an alkyl group, it has the value zero and R R and R havfe the significance hereinbefore described can be prepared in the follow ng manner. Using. the procedure of Salway, J. Chem. Soc. 1 03', 3514-61- (1913) (see also US. Patent 2,821,532}; a Grigna'rd reagent derived from indole is reacted with an a-haloacyl halide having from three to eight carbon" atoms, the halogen being chlorine or bromine. There is thus produced a 3- indolyl l-haloalkyl ketone and there may also be produced a l-(haloaoyD-Iadndolyl l' haioalltyl ketone, The 'l-(halo-acyl) substituent inthe latter compound can'be of the formula R R NH wherein R a-iidH have the significance hereinbefore described, to obtain a ketone of the formula:

wherein R represents an alkyl radical. Alternatively, the

same ketone can be obtained by reacting thel-(haloacyl-3 -indolyl l-haloalkyl ketone described abovelwith an amine R R NH, thel-(haloacyl) substituentbeing elimi nated from the molecule duringfthe reaction. The ketone of Formula. IV can then be alkylated, for example,

using the procedure described in copen'ding application Serial No. 533,882, filed September 12, 1955, or that described by Schmitt, Suget and Fallard, BHJLSOQ. Chim,, France, 1470 (1957), for the l-alkylati'on ofL3-indolyl ketones, to obtain a ketone of theformulaz. V

wherein R represents an alkyl radical and; R R and and products of the present-invention, but are not to be construed as limiting,

Emmi? oxide- A, mixture of three-grams. nominee of: neon-3.42; dimethylamino-lrhydroxyethyl)indole (US. Patent 2,-

825,734), fifty milliliters 0t absolu e ethanol:- and 1.6 'milli liters (0.013; mole): of29 percent hydrogenperoxide Was allowed to standj-for four days. at. a. temperature otap proximately twenty degrees. entigrade. he; e u i solution was, shaken, with 0.0.7.5 gramiofplatinumordde for 2.5-hours. The platinumh-oxidewascremoved byfiltra tion and the filtrate was, concentrated by distillationsunder reduced pressure, The viscous residue, was; crystallized .frorn ethyl acetate and resulting crystallinmmaterial was isolated and dried in a vacuum oven. There was thus obtained 2.3 grams of 1-ethyl-3-(2-dimethylamino- 1-hydroxyethy1)indole N-oxide (as the monohydrate) in the form of a crystalline solid which had a softening point of 44 degrees centigrade and a melting point of 74 to 84 degrees centigrade.

Analysis.-Calcd. for C H N O C, 63.13; H, 8.33; N, 10.53. Found: C, 63.57; H, 8.22; N, 10.46.

EXAMPLE 2 1-methyl-3-(Z-dimethylamino-I-hydroxethyl) indole N- oxide A mixture of 2.5 grams (0.0115 mole) of 1-methyl-3- (Z-dimethylamino-l-hydroxyethyl) indole (U.S. Patent 2,- 825,734), fifty milliliters of absolute ethanol and 1.3 milliliters (0.011 mole) )of thirty percent hydrogen peroxide was allowed to stand for four days at approximately twenty degrees centigrade. The resulting solution was shaken with 0.6 gram of platinum oxide for two hours. The platinum oxide was removed by filtration and the filtrate was concentrated by distillation under reduced pressure. The residue was crystallized from ethyl acetate and the resulting crystalline material was isolated and dried in vacuo over phosphorus pentoxide. There was thus obtained 1.8 grams of 1-methyl-3-(2-dimethylaminol-hydroxethyDindole N-oxide in the form of a crystalline solid which gradually softened between eighty and 146 degrees centigrade and which had a melting point of 148 to 152 degrees centigrade.

Analysis.-Calcd. for C H N O C, 66.64; H, 7.74; N, 11.95. Found: C, 66.21; H, 7.72; N, 12.25.

EXAMPLE 3 1 -methyI-3-(2-morpholino-1 -hydroxyelhyl) indole N oxide In the same manner described in Example 1, but substituting 1-methyl-3-(2-morpholino-1-hydroxyethyl)indole (U.S. Patent 2,825,734) for 1-ethyl-3-(2-dimethylamino- 1-hydroxyethyl)indole, there was obtained 1-methyl-3-(2- morpholino-l-hydroxyethyl)indole N-oxide.

EXAMPLE 4 1-isopropyl-3-(Z-dimethylamino-I-hydroxyethyl) indole N-oxide In the manner described in Example 1, but substituting 1-isopropyl-3-(Z-dimethylamino-1 hydroxyethyl)indole (U.S. Patent 2,825,734) for 1-ethyl-3-(2-dimethylamino-l-hydroxyethyDindole, there was obtained 1-iso-- propyl-3-(2 dimethylamino 1 hydroxyethyl)indole N- oxide.

EXAMPLE 5 1-nrbutyl-3-(2-dimethylamino-1 -hydroxyethyl)indole N- oxide In the manner described in Example 1, but substituting 1-n-butyl-3-(2-dimethylamino-l-hydroxyethyl)indole (U.S. Patent 2,825,734) for 1-ethyl-3-(2-dimethylamino- 1-hydroxyethyl)indole there was obtained 1-n-butyl-3-(2- dimethylamino-l-hydroxyethyDindole N-oxide.

EXAMPLE 6 1-n-hexyl-3- (Z-dimethylamino-Z-hydroxyethyl) indole N oxide In the same manner described in Example 1, but substituting 1-n-hexyl-3-(2-dimethylarnino-l-hydroxyethyl) indole (U.S. Patent 2,825,734) for 1-ethyl-3-(2-dimethylamino-1-hydroxyethyl)indole, there was obtained l-nhexy1-3-(2 dimethylamino 1 hydroxyethyl)indole N- oxide.

EXAMPLE 7 1-methyl-3-(3-dimethylamino-1-hydr0xypropyl) indole N- oxide A. PREPARATION OF 1-METHYL-3-(3-DIMETHYLAMINO- PROPIONYL) INDOLE A mixture of 13.6 grams (0.0785 mole) of 1-methyl-3- of ether.

degrees centigrade) 6 acetylindole, 6.4 grams (0.0785 mole) of dimethylamine hydrochloride, 3.54 grams (0.118 mole) of paraformaldehyde and fifty milliliters of absolute ethanol was heated under reflux for 27 hours. The solution was evaporated under reduced pressure and finally in vacuo, and the solid residue was recrystallized twice from a mixture of methanol and ether. There was thus obtained 11.4 grams (second crop; 0.55 gram) of 1-methyl-3-(3- dimethylaminopropionyl)indole hydrochloride in the form of a crystalline solid having a melting point of 186 to 187 degrees centigrade.

Analysis.Calcd. for C14H18N20'HC1: C, 63.03; H, 7.35; Cl, 13.29; N, 10.50. Found: C, 62.81; H, 6.93; Cl, 13.33; N, 9.96.

B. PREPARATION OF 1-METHYL3-(3-DIMETHYLAMINO- 1-HYDROXYPROPYL)INDOLE A solution of 3.3 grams (0.012 mole) of 1-methyl-3-(3- dimethylaminopropionyl)indole hydrochloride in fifteen milliliters of methanol was added to an ice-cold solution of 3.5 grams (0.092 mole) of sodium borohydride in twenty milliliters of methanol. The mixture was cooled in ice and stirred for fifteen minutes, then stirred for a further nineteen hours at room temperature (approximately twenty degrees centigrade). The resulting mixture was cooled in ice, diluted with milliliters of water and extracted with three portions, each of 100 milliliters, The combined ethereal extracts were washed with water and with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue was dissolved in a mixture of 75 milliliters of methanol, ten grams of potassium hydroxide and 25 milliliters-of water and the solution was heated under reflux for two hours. The solution was evaporated :to dryness in vacuo and the residue was extracted with three portions, each of 100 milliliters, of ether. The combined ethereal extracts were washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The crystalline residue was recrystallized from a mixture of ether and petroleum ether (boiling range thirty to sixty There was thus obtained l-methyl-3-(3-dimethylamino 1 hydroxypropyl)indole in the form of a crystalline solid which had a melting point of 87.5 to 88.5 degrees centigrade.

Analysis.Calcd. for C H N O: C, 72.37; H, 8.68; N, 12.06. Found: C, 72.76; H, 8.64; N, 12.18.

C. PREPARATION OF 1-METHYL-3-(S-DIMETHYLAMINO- l-HYD ROXYPROPYL) INDOLE N-OXIDE Using the procedure described in Example 1, but substituting 1-methyl-3-(3-dimethylamino-l-hydroxypropyl)- indole for 1-ethyl-3-(Z-dimethylamino-l-hydroxyethyl)- indole, there was obtained 1-methyl-3-(3-dimethylaminol-hydroxypropyl) indole N-oXide as a crystalline solid which softened at about 103 degrees centigrade, resinified at about to 116 degrees centigrade, and then slowly melted up to about degrees centigrade.

Ana'lysis.-Calcd. for C H N 0 N, 11.28. Found: N, 11.10.

EXAMPLE 8 1 ethyl 3 (2 dimethylamino 2 methyl 1 h droxyezhyDindole N-oxide l-bromoethyl 1-(2-bromopropionyl)-3-indo1yl ketone (U.S. Patent 2,821,532, Example 2) was reacted with dimethylamine by the procedure described in said Example 2 of said patent to yield l-dimethylaminoethyl 3- indolyl ketone. The latter ketone was alkylated using ethyl iodide in the presence of potassium carbonate according to the procedure described in copending application Serial No. 533,882, filed September 12, 1955, to produce l-dimethylaminoethyl l-ethyl-3-indolyl ketone. This ketone was reduced using sodium borohydride in methanol to 1-ethyl-3-(2-dimethylamino-2-methyl-l-hydroxyethyl)ind0lc which was converted to 1-ethy1-3-(2- 7 "thereof? by the procedure described in Example 1. It is to be understood that theinvention is not to'be limited to the exact details of operation or exact coinpound shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims. r Y

I claim: 1. A compound selected from the group consisting of (1) a compound having the formula I wherein R and R taken individually represent alkyl radicals containing from one to'six carbon atoms, and R 'and R taken together with -N form a heterocyol-ic amino radical selected from the class consisting of pyrrolidino, 2-methylpyrrolidino, 2,2-dimethylpyrrolidino, piperidino; methylpiperidino, 'ethylpiperidino, morpholino, thiamorpholino, and hexamethylen'eimino, R is se-' lected from the group consisting of hydrogen and an alkyl radical containing from one to six carbon atoms, R represents an alkyl radical containing from one to six .carbon atoms, and n is an integer from zero to one; and (2) pharm colo'gie'al-ly acceptable acid addition salts dimethylamino-Lmethyl-1-hydroxyethyl)indole V 'N-oxide V 8 2. 1 ethyl 3 (2 dimethylaminos-s 1 hydroxy-w ethyl)indole N oxide. l 7 I 1, 3. 1 methyl 3 (2 dimethylamino -"1' water ethyl)indole N-oxide. l s' 4. l methyl 3 (2 morpholi-nof 1 v-lhydroxy ethyl)indole N-oxide. 7 a 5. 1 isopropyl 3 (2 dimethylamino 1 liyidroxyethyDindole N-oxide. 1

6. 1 n butyl 3 (2 dimethylamino 1 hydroxy- 10 ethyl)indole N-oxide.

'7. 1 n hexyl 3 2 'dimethylamino liydroity ethyl)indole N-oxide. 1 a W 8. l methyl 3 3 dimethylamino -fhydroxyp propyl)indole N-oxide. D

V 9. 'l'- ethyl 3 5 '(2- dimethylamino- 2' -"met hylf hydrOxyethyDindole N-oxidei -v w 7 'References Cited in the .i ilof This patent i UNITED STATESPAT-ENTS 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) A COMPOUND HAVING THE FORMULA 